The adaptive immune cells also play important role in proper function of the central neural system (CNS). However, their role in Alzheimer's disease (AD) remains poorly understood even though a risk for dementia and AD increases together with the dysregulation of immune cells in the elderly. Although our previous results suggest that that B cells can alleviate AD symptoms via generation of Ab plaque-neutralizing antibody (Olkhanud et al, Vaccine, 2011), here report that B cells can be pathogenic in 2 types of mice that develop AD in young and old age, 2xTgAD and 3xTgAD mice, respectively. The mice were crossed with B-cell deficient (BKO) mice to generate 2xTgAD/BKO and 3xTgAD/BKO mice. Our results reveal that the loss of B cells in these mice appears to alleviate AD. Compared to age/sex-matched B-cell sufficient littermates, 3xTgAD/BKO mice exhibit less anxiety and improved memory deficits. Despite high levels of APP production in neurons, 3xTgAD/BKO mice contain significantly fewer Ab-plaques in the brain subiculum than age-matched 3xTg-AD mice. The over activated microglia in 3xTgAD mice, another hallmark of AD pathology, is markedly reduced in age/sex-matched 3xTgAD/BKO mice. We confirmed these results by transiently depleting B cells in 3xTgAD mice, which ameliorates AD. Overall these results for the first time indicate a pathogenic role of B cells in AD. Overall, the study is progressing as planned. Our current aim is to elucidate the mechanism how B cells exacerbate AD in aging.Our preliminary results suggest that B cells appear to facilitate aging-associated onset of AD by targeting inflammatory immune cells and affecting Trp pathway.